1. Field of the Invention
The present invention relates to polymers which are useful in extending the in vivo circulating life of biologically active materials. The invention also relates to conjugates made with the polymers.
2. Description of Prior Art
Some of the initial concepts of coupling peptides or polypeptide to poly(ethylene glycol) PEG and similar water-soluble poly(alkylene oxides) are disclosed in U.S. Pat. No. 4,179,337, the disclosure of which is incorporated herein by reference. Polypeptide modified with these polymers exhibit reduced immunogenicity or antigenicity and circulate in the bloodstream longer than unmodified versions.
To conjugate poly(alkylene oxides), one of the hydroxyl end-groups is converted into a reactive functional group. This process is frequently referred to as "activation" and the product is called an "activated poly(alqylene oxide)". Other substantially non-anitigenic polymers are similarly "activated" or fimctionalized.
The activated polymers are reacted with a therapeutic agent having nucleophilic functional group(s) that serve as attachment site(s). One nucleophilic functional group commonly used as an attachment site is the epsilon-amino group of lysines. Free carboxylic acid groups, suitably activated carbonyl groups, oxidized carbohydrate moieties, hydroxyl and mercapto groups have also been used as attachment sites.
Over the years, one shortcoming observed with polymer conjugation is that the conjugate has a different pI than the unmodified protein, enzyme, etc. For example, pegylation, i.e. attachment of the polymer, of lysine amino groups result in a decrease in the isoelectric point and changes the pH optimum, i.e the pH at which maximum bioactivity is observed. In some cases, it would be beneficial to restore the original pI or even alter the pI value of the polymer conjugate in order to optimize bioactivity at physiologic pH.
The present invention provides solutions to this problem.